Latent class analysis to evaluate performance of point-of-care CCA for low-intensity Schistosoma mansoni infections in Burundi

Abstract

BackgroundKato-Katz examination of stool smears is the field-standard method for detecting Schistosoma mansoni infection. However, Kato-Katz misses many active infections, especially of light intensity. Point-of-care circulating cathodic antigen (CCA) is an alternative field diagnostic that is more sensitive than Kato-Katz when intensity is low, but interpretation of CCA-trace results is unclear. To evaluate trace results, we tested urine and stool specimens from 398 pupils from eight schools in Burundi using four approaches: two in Burundi and two in a laboratory in Leiden, the Netherlands. In Burundi, we used Kato-Katz and point-of-care CCA (CCAB). In Leiden, we repeated the CCA (CCAL) and also used Up-Converting Phosphor Circulating Anodic Antigen (CAA).MethodsWe applied Bayesian latent class analyses (LCA), first considering CCA traces as negative and then as positive. We used the LCA output to estimate validity of the prevalence estimates of each test in comparison to the population-level infection prevalence and estimated the proportion of trace results that were likely true positives.ResultsKato-Katz yielded the lowest prevalence (6.8%), and CCAB with trace considered positive yielded the highest (53.5%). There were many more trace results recorded by CCA in Burundi (32.4%) than in Leiden (2.3%). Estimated prevalence with CAA was 46.5%. LCA indicated that Kato-Katz had the lowest sensitivity: 15.9% [Bayesian Credible Interval (BCI): 9.2–23.5%] with CCA-trace considered negative and 15.0% with trace as positive (BCI: 9.6–21.4%), implying that Kato-Katz missed approximately 85% of infections. CCAB underestimated disease prevalence when trace was considered negative and overestimated disease prevalence when trace was considered positive, by approximately 12 percentage points each way, and CAA overestimated prevalence in both models. Our results suggest that approximately 52.2% (BCI: 37.8–5.8%) of the CCAB trace readings were true infections.ConclusionsWhether measured in the laboratory or the field, CCA outperformed Kato-Katz at the low infection intensities in Burundi. CCA with trace as negative likely missed many infections, whereas CCA with trace as positive overestimated prevalence. In the absence of a field-friendly gold standard diagnostic, the use of a variety of diagnostics with differing properties will become increasingly important as programs move towards elimination of schistosomiasis. It is clear that CCA is a valuable tool for the detection and mapping of S. mansoni infection in the field and CAA may be a valuable field tool in the future.Electronic supplementary materialThe online version of this article (10.1186/s13071-018-2700-4) contains supplementary material, which is available to authorized users.

Is POC-CCA a truly reliable test for schistosomiasis diagnosis in low endemic areas? The trace results controversy

“…Usually, the bottleneck is the use of the low-sensitivity Kato-Katz test as a “gold standard.” Interpretation of trace as positive (presence of infection) or negative (absence of infection) creates lots of discussion about the validation of POC-CCA as a single test to replace Kato-Katz for the estimation of schistosomiasis prevalence in transmission areas. Particularly concerned with POC-CCA performance in low endemic areas, Clements and colleagues [ 17 ] evaluated trace results by applying Bayesian latent class analysis to improve the low sensitivity of the Kato-Katz and the so-called absence of a “gold standard.” In the same study, up-converting phosphor lateral flow circulating anodic antigen (UCP-LF CAA), a non-commercially available assay, was used to evaluate preselected trace-positive POC-CCA samples by assuming UCP-LF CAA was 100% specific. The results showed that POC-CCA outperformed Kato-Katz.…”

When Should the Emphasis on Schistosomiasis Control Move to Elimination?

“…In areas that have control programs that have achieved very low levels of prevalence and intensity, such as Egypt, or areas that once had schistosomiasis but appear to have eliminated S. mansoni transmission, the use of the POC-CCA assay indicates approximately 5–10% trace positive results. Some of these can be attributable to very, very low-level infections, but many are likely false positives [ 23 ]. Thus, the POC-CCA is not an adequate tool for validating elimination of transmission, and additional work is needed to define the sampling strategies, tests, and results to confirm that transmission has been interrupted [ 24 ].…”

Diagnosis of Schistosoma mansoni infections: what are the choices in Brazilian low-endemic areas?

“…Applying LCA enables straightforward assessment of the prevalence estimates from each test by comparing the distributions of estimated test and estimated infection prevalence. 48 , 93 The introduction of statistical LCA is encouraged, as it yields more accurate sensitivities and specificities of new tests than those obtained by comparisons to an imperfect gold standard. 93 …”

“… 48 , 93 The introduction of statistical LCA is encouraged, as it yields more accurate sensitivities and specificities of new tests than those obtained by comparisons to an imperfect gold standard. 93 …”